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GWAS in Crohn's disease
Introduction Genome-wide association study (GWAS) is an approach used in genetics research to associate specific genetic variations with particular diseases. The method involves genome sequencing of normal people and people affected with a particular disease, looking for genetic markers that can be used to understand which genes contribute to the disease and develop better prevention and treatment strategies. Data generated by labarotories all over the world is compiled by the National Institutes of Health, a catalog of published GWAS can be found at http://www.cdc.gov/genomics/hugenet.(1). Crohn's disease Crohn's disease (CD) is a chronic disease characterized by recurring inflammation of the gut, it is thought to arise in response to the commensal microflora in a genetically susceptible host. Symptoms include (bloody) diarrhea, abdominal discomfort, weight loss and anemia. Arthritis, eye and skin disorders have also been described in patients with CD. CD is a major burden of healthcare services, with a prevalence of 100 to 150 cases per 100,000 persons per year in the western world and with a peak age of onset between 10 and 30 years of age. CD is partly heritable; as demonstrated in the higher concordance rate in monozygotic twins (56%) compared with dizygotic twins (4%). (2,3) Prior to the introduction GWAS only the genes NOD2 and IL2 had unequivocally been associated with CD. Using GWAS Rivas et al. identified another 71 genetic variants associated with CD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. (4,5) GWAS in Crohn's disease patients To investigate genetic variance in CD patients, Rivas studied 350 controls and 350 CD individuals. His group extracted DNA from all samples; PCR amplified the coding exons in each sample and then sequenced the products by next generation sequencing. The most challenging part of the GWAS project was the data processing and analysis. The billions of sequences generated by next generation sequencing were analyzed with software developed at MIT. The software analyzed SNP calling on pooled data, estimated allele frequencies of discovered variants, applied single-marker association tests in a pooled setting, carried out group-wise testing of rare and low-frequency variants, performed power evaluation and quality control summary, and annotated variants discovered in regions from primary sequencing data in Sequence Alignment/Map format. Using this analysis, researchers identified which variants and regions could be considered regions of interest.(6) Conclusion CD is a complex genetic disorder with an estimated heritability of 50% and it is characterized by a recurring inflammation of the gastrointestinal tract. Using GWAS led to the discovery of 71 risk loci, which have improved our understanding of the disease pathogenesis. At the moment, approximately 23% of the heritability can be explained. Meta-analysis of GWAS data may allow the identification of other genes involved in CD. References 1. http://www.cdc.gov/genomics/hugenet 2. http://www.crohnsandcolitisinfo.com/ 3. http://omim.org/entry/266600 4. Rivas M et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. 2011. Nature Genet.43:11.1066-1073. 5. Fransen K et al. The quest for genetic risk factors for Crohn's disease in the post-GWAS era. Genome Med. 2011; 3(2): 13. Published online Feb 25, 2011. doi: 10.1186/gm227 PMCID: PMC3092098 6.http://www.broadinstitute.org/ftp/pub/mpg/syzygy/MARV.R 7. McGovern DP et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nature Genet. 42: 332-337, 2010 Note: Erratum: Nature Genet. 43: 388 only, 2011. Text: Nature Publishing Group